Transcript GRECC Genetics of Alzheimer`s 2013 10-4

The Genetics
Of
Alzheimer’s
Sue Griffin, PhD
Dillard Professor and Vice Chair
Donald W. Reynolds
Department of Geriatrics
University of Arkansas
For Medical Sciences
Research Director
GRECC VAMC
Little Rock, Arkansas
Genes are on
chromosomes
present in the
nucleus of
every cell
The genetic code has four letters:
A=adenine, T=thymine, G=guanine, C=cytosine
Chromosomes
in the nucleus
The yellow ribbon is
held together by A—T
and C—G
Chromosomal
DNA (genes)
carry the code
for all proteins
necessary to
make our body
Facts:
• A complementary strand (messenger RNA) is made
to nuclear DNA—an A on the mRNA is paired
with a T on the gene and C with G, over and over
to code for the building blocks (amino acids)
needed to make every protein!
• Every amino acid has a unique code
Diversity of Genetic Diseases
Simplistic:
• One gene mutation causes every case.
More Complex:
• Multiple gene mutations cause all cases.
Most Complex:
• Multiple gene mutations cause some cases.
• Multiple polymorphisms increase risk.
• Multiple environmental factors increase risk.
What Starts Everything
Going Wrong
In Alzheimer’s Disease?
• The genes you inherit (nature)
• Wear and tear of time (aging)
• The way you handle
your inheritance (nurture)
When You’re
Old but Okay
Nerve Cells and
How They Work
In Normal Brain
• The nucleus
• The cytoplasm
• The processes
• The transmission
of information
When your brain is hot and fine
Progression from Hearing to
Speaking and from Reading to
Mulling It All Over
Affected Regions at Different
Stages of Alzheimer’s Disease
MILD
MODERATE
SEVERE
When the Brain “Cools Down”
Clincally Normal
Alzheimer’s disease
The Problem in
Alzheimer’s
Disease from
One of His
Own Cases
MB Graeber 1997 Neurogenetics
*Plaques in Alzheimer Brain
10 µm
Aβ plaques, activated glia, neuronal DNA
What is that sticky insoluble
stuff in plaques?
• The b-pleated sheet protein b-amyloid (Ab)
• George Glenner sequenced the protein and Konrad
Beyreuther, Dmitry Goldgaber, and St. George-Hyslop
and colleagues mapped the Ab precursor protein
(bAPP) gene to chromosome 21
• This is important!!
bAPP is Cleaved
to Form b-amyloid
Functions of bAPP
• Responds to injury
• Membrane Functions
• Interacts with PS1
Reasoning Behind This Discovery?
Fact:
• People with Trisomy 21 have Alzheimer Ab
plaque pathology by middle age (Wisniewski, 1989)
Hypothesis:
• Plaques in Down’s as in Alzheimer’s are the
product of bAPP cleavage, so it’s logical that
mutations in bAPP cause the disease in families
with lots of Alzheimer’s. Tanzi and others took this
candidate gene approach (Plan A in genetic studies).
Plan A - Sequence a Specific Gene
Studies of Alzheimer families that were based
on a pathological characteristic of the disease
• Because Ab plaques were the most prominent
neuropathological feature, bAPP was the targeted
gene in AD in these families.
• At least three offending bAPP mutations in DNA
from family members have been identified by
searching for mutations by mapping of this gene.
bAPP Mutations
Cause Alzheimer’s
Disease
. . How did we come to know this??
We thought that we
were nearly there!
The cause! Yes!
But that was only 1989 and . . .
Family Association Studies
• Then they asked: Do all family members
with the mutation have the disease? Yes
• Do family members who don’t have the
mutation have the disease? No (Maybe?)
If yes on the first and no on
the second = Disease associated,
Causative, and Dominant!
Hmm ~ Why Maybe
Not all familial Alzheimer’s disease
families have mutations in this gene
And all of the known bAPP mutations
taken together don’t account for all of
the people (>5%) with
familial Alzheimer’s
So Plan B - Mapping Studies Identified Two Other Causative Genes
• Taking a more unbiased approach—that is, not
looking for a missense sequence in a specific
protein—researchers used endonucleases to
cleave DNA for restriction fragment length
polymorphism (RFLP) studies to identify aberrant
cleavage sites. This type of chromosome mapping,
identified two more mutated genes (Presenilin-1
and -2) that, like bAPP mutations, are causative
for Alzheimer’s disease.
Notes on RFLP Studies
• Restriction endonucleases are enzymes
that cleave DNA at specific sites.
• Absence of a cleavage site can be used
to identify a missense or mutated site
Plan B Also Identified one of three
Apolipoprotein E polymorphisms (e 4)
Associated with Increased Alzheimer Risk
• RFLP mapping of DNA from a case
control study identified a chromosome 19
region that associated with, but not
causative of, Alzheimer’s disease. The
variant was ApoE e4.
Mutations:
Several in the bAPP Gene
Presenilin 1 and 2 Genes
Copy Number:
bAPP e.g. Down’s syndrome
Polymorphisms:
Apolipoprotein E Genes
Inflammatory Genes
ApoE Facts
• ApoE is important in transport of lipoproteins.
But its specific role in neurons is unknown.
• There are three variants—e2, e3, and e4.
• The ApoE ε4 gene carries a high relative risk:
• Inheritance of e4 increases Alzheimer risk 3-9X.
• More than half of Alzheimer patients have one
or more e4 alleles.
• Inheritance of the e2 allele may be protective.
Some ApoE 2, 3, and 4 Facts
These isoforms differ from each other only by single amino
acid substitutions at positions 112 and 158 of the 299 amino
acid protein but have profound physiological consequences.
E2 is uncommon but is associated with both increased and
decreased risk for atherosclerosis. Approximately 64 percent
of the population carries one or two E3 genes. E3 is the
"neutral" Apo E genotype. E4 has been implicated in atherosclerosis and Alzheimer's disease, impaired cognitive
function, and reduced neurite outgrowth. ApoE is a target
gene of liver X receptor, a nuclear receptor member that plays
a role in metabolic regulation of cholesterol, fatty acid, and
glucose homeostasis. Look in Wikipedia
bAPP is Cleaved
to Form b-amyloid
Functions of bAPP:
• Expression increases
in response to injury
and in aging
• Membrane Functions
• Interacts with PS1
ApoE Regulates bAPP Expression
Neurons
In Culture
ApoE3 ApoE4
Alzheimer
Brain
Plaque proximity = less neuronal bAPP
Ab bAPP Nuclei
One Important Driver
A neuroinflammatory Cytokine
named interleukin-1 (IL-1).
Why would I say that?
What can IL-1 drive?
What Does IL-1 Do?
• To Neurons
Increases production of:
i) bAPP
ii) Faulty tau (hyperphosphorylated)
iii) Enzymes that breakdown
neurotransmitters
Decreases production of:
i) synaptophysin
Neurofibrillary
Tangles
(red)
IL-1 in
Microglia
(green)
Interleukin-1 has a
Sister Cytokine ~ TNFa
1.TNF and IL-1 are both elevated
in Alzheimer’s disease.
2. They induce each other and act
as neuroinflammagens.
3. Both act as gliotransmitters.
Yes
Are their heritable variants of the genes
that encode these drivers that might
increase risk for Alzheimer’s disease?
Probably
IL-1 Genotype and Age at
Alzheimer’s Onset
Factor
ApoE e4
IL-1A 2,2
Odds Ratio
5.5
4.9
Grimaldi, Griffin, et al. Ann Neurol, 2000
Confirmation of an Old Idea
1. Breitner JC et al Neurology 1994;44:227
2. in ’t Veld BA et al Neurobiol Aging 1998;19:607
3. Zandi PP et al Neurology 2000;54:2066
4. Vlad SC et al Neurology 2008;70:1672
5. Szekely, C. A. Neurology 2008;70:17
Adjusted odds ratios of Alzheimer’s
for ibuprofen ( ) and naproxen ( )
Combat Strategies
•Prevention:
Exercise
Diet and Stop Smoking
Combat Inflammation
•Treatment:
Education and Cognitive Reserve
Meds: Aricept, Namenda
We
are
our
genes
But we get to decide what we do about our genetics!